[unreadable] The long term goals of this research are to develop a multidisciplinary research program that provides a systematic, rational, three dimensional approach to the design and synthesis of potent receptor/acceptor selective peptide and peptide mimetic ligands for peptide hormones and neurotransmitter G-protein coupled receptors (GPCRs). This research requires a highly multidisciplinary approach including: computer assisted modeling; conformational analysis using 2D NMR spectroscopy and other biophysical methods; novel asymmetric synthetic methods; macrocyclic peptide and peptidomimetic synthetic methods; the utilization of cloned GPCRs for binding and second messenger assays; and for evaluation of conformation-biological activity relationships that lead to receptor selective and potent peptides and peptidomimetics with specific agonist and antagonist biological activities; to develop a new biophysical method, plasmon waveguide resonance (PWR) spectroscopy that allows for the first time direct observation of the structural changes that accompany ligand-GPCR interactions in membranes. Specifically, this grant will focus on ligands which are derived from proopiomelanocortin (e.g. alpha-MSH, gamma-MSH, etc.), and that interact with human melanocortin receptors MC1R, MC3R, MC4R and MC5R. Specific aims include: 1) development of novel asymmetric synthetic methods for conformationally and topographically constrained novel amino acids, chimeric amino acids, beta-turn mimetics, and other templates for design of novel peptide and peptide mimetic melanotropins; 2) to develop novel, potent and selective structures which are ligands for the hMC1R, hMC3R, hMC4R and hMC4R; 3) to use stable transfected cell lines to evaluate ligand-receptor binding affinities, second messenger activities, and other bioactivities; 4) to use computer assisted modeling, computational chemistry, conformational analysis and related methods to develop and test models of agonist and antagonist bioactivity; 5) to develop PWR spectroscopy into a powerful tool for examining in real time the structural differences of ligand receptor complexes that are respectively agonist, antagonist, or inverse agonist induced; 6) finally we will work closely with biologists and others worldwide to develop novel insights into the bioactivities of melanotropins and melanocortin receptors (pigmentation, feeding behavior, sexual behavior, immune response, pain, etc.). [unreadable] [unreadable]